1-,2-,3-,4-,5-,6-,7-,8- and/or 9 substituted dibenzoxazepine compounds, pharmaceutical compositions and methods for treating pain

ABSTRACT

The present invention provides substituted dibenzoxazepine compounds of Formula I:  &lt;IMAGE&gt;  which are useful as analgesic agents for the treatment of pain, pharmaceutical compositions comprising a therapeutically-effective amount of a compound of Formula I in combination with a pharmaceutically-acceptable carrier, and a method for eliminating or ameliorating pain in an animal comprising administering a therapeutically-effective amount of a compound of Formula I to the animal.

BACKGROUND OF THE INVENTION (1) Field of the Invention

The present invention generally relates to compounds havingpharmacological activity which are useful as pharmaceutical agents and,more particularly, as analgesic agents for the treatment of pain, topharmaceutical compositions containing one or more of these compounds,and to methods of treatment employing these compounds. Moreparticularly, the present invention concerns substituted dibenzoxazepinecompounds, pharmaceutical compositions containing one or more of thesecompounds in combination with a pharmaceutically-acceptable carrier, andmedical methods of treating pain employing these compounds.

Analgesic compounds are agents which alleviate pain without causing aloss of consciousness and, thus, which are useful for treating pain and,often, for reducing inflammation.

The major classes of analgesic compounds include narcotic analgesics, oropiates, compounds which alleviate pain and induce sleep, andanalgesic-antipyretic compounds, compounds which alleviate pain andreduce fever, such as salicylates.

Although the efficacy of opiates in relieving pain is well established,the associated addiction liability of opiates is a distinct disadvantageof these compounds.

While salicylate and salicylate-like agents (non-steroidalantiinflammatory agents or NSAIDS) are also efficacious in relievingpain, they often exhibit undesirable side effects, such asgastrointestinal irritation, as with aspirin, allergic response, as withaspirin, and/or liver toxicity with extended use, as with acetaminophen.

The compounds of the present invention are neither opiates norsalicylates, and represent another class of compounds which are usefulas analgesic agents.

(2) Description of the Related Art

U.S. Pat. Nos. 4,559,336 and 4,614,617 (a continuation-in-part of U.S.Pat. No. 4,559,336) disclose 8-chlorodibenz[b,f] [1,4]-oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containingacyl)hydrazides, and intermediates thereof.

U.S. Pat. No. 3,534,019 discloses hydrazides of dibenzoxazepine-,dibenzothiazepine- and dibenzodiazepine- carboxylic acids.

U.S. Pat. No. 3,624,104 discloses aralkanoyl derivatives ofdibenzoxazepine-N-carboxylic acid hydrazide compounds.

U.S. Pat. No. 3,989,719 discloses N,N'-diacyl hydrazines.

U.S. Pat. Nos. 3,917,649 and 3,992,375 (a divisional of U.S. Pat. No.3,917,649) disclose dibenzoxazepine N-carboxylic acid hydrazinecompounds.

U.S. Pat. Nos. 4,045,442, 4,125,532 (a divisional of U.S. Pat. No.4,045,442) and 4,170,593 (a divisional of U.S. Pat. No. 4,125,532)disclose 1-(substitutedamino)alkanoyl-2-(dibenzoxazepine-10-carbonyl)hydrazine compounds.

U.S. Pat. No. 4,559,337 discloses 8-chlorodibenz-[b,f][1,4]-oxazepine-10(11 H)-carboxylic acid, 2-(alkoxy-containingacyl)hydrazide compounds.

GB 1 522 003 discloses 1-acyl-2-(8-chloro-10,11-dihydrodibenz [b,f][1,4]oxazepine-10-carbonyl)hydrazine compounds.

GB 1 331 892 discloses derivatives of dibenzoxazepine N-carboxylic acidhydrazides.

European Patent Application Publication No. 0 012 385 disclosesdibenz[b,f] [1,4]oxazepine derivatives.

German Patent Application Publication No. 1,170,322 discloses10-substituted dibenz[b,f][1,4]oxazepine-11(10 H)-ones.

European Patent Application Publication No. 0 193 822 discloses8-chlorodibenz[b,f][1,4]-oxazepine-10(11 H)-carboxylic acid, 2-(thio-,sulfinyl- and sulfonyl-containing acyl)hydrazide compounds.

European Patent Application Publication No. 0 218 077 discloses8-chlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[(substituted phenylsulfinyl)alkanoyl]hydrazide compounds and8-chlorodibenz [b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[(substituted phenylsulfonyl)alkanoyl]hydrazide compounds, andintermediates used in the preparation of these compounds.

Netherlands Patent No. 67,00603 discloses substituteddibenz[b,f][1,4]oxazepine-11(10H)-one compounds.

Drower et al., "The Antiociceptive Effects of Prostaglandin Antagonistsin the Rat," European Journal of Pharmacology, 133, 249-256 (1987),disclose the study of the antinociceptive properties of two competitiveantagonists of prostaglandins of the E series,8-chlorodibenz[b,f][1,4]-oxazepine-10(11 H)-carboxylic acid,2-acetylhydrazide and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-(5-chloro-1-oxopentyl)-hydrazide.

J. H. Sanner, "Dibenzoxazepine Hydrazides as Prostaglandin Antagonists,"Intra-Science Chem. Rept., 6(1), 1-9 (1972), describes experimentsperformed with two dibenzoxazepine derivatives designated SC-18637 andSC-19220, and shown below, and found that SC-18637 and SC-19220 inhibitthe stimulant actions of prostaglandins on isolated smooth musclepreparations. ##STR2##

K. Nagarajan et al., "Synthesis of 10,11-Dihydrodibenz[b,f][1,4]oxazepine Derivatives as Potential Anticonvulsants &Psychotropic Agents," Indian Journal of Chemistry, 24B, 840-844 (1985),disclose the synthesis of acyl, carbamoyl and thiocarbamoyl derivativesof 10,11-dihydrodibenz [b,f][1,4]oxazepine, most of which have either anitro or an amino group at position-2, as analogues of carbamazepine,and the evaluation of these derivatives as anticonvulsants associatedwith neuroleptic activity.

Other art which relates to the present invention includes that which isdiscussed below.

D.E. MacIntyre et al., "Antagonism of Human Platelet Responses toStimulatory and Inhibitory Prostaglandins," Prog. Lipid. Res., 20(1-4),453-9 (1981), disclose on Page 454, Lines 11-12, Page 458, Lines 43-44,and in Table 1, two dibenzoxazepine compounds designated SC-19220 andSC-25191, and shown above and below, respectively, which were employedin an investigation of the effects of prostaglandin antagonists onplatelet responses to stimulatory and inhibitory prostaglandins.##STR3##

R. Gimet et al., "Quantitative Determination of Polymorphic Forms in aFormulation Matrix Using the Near Infra-Red Reflectance AnalysisTechnique," J. Pharmaceutical & Biomedical Analysis, 5(3), 205-211(1987), disclose an analytical method for the determination of thepolymorphic transformation of an active ingredient in a solid dosageform matrix, and discuss a compound designated SC-25469, and shownbelow, at Page 206, Lines 16-23. ##STR4##

J.H. Sanner et al., "Structure-Activity Relationships of someDibenzoxazepine Derivatives as Prostaglandin Antagonists," Advances inthe Biosciences, 9, 139-148 (1972), disclose tests for prostaglandinantagonism on isolated guinea-pig ileum and rat stomach fundus stripswith the n-butanoyl, i-butanoyl and n-hexanoyl analogs of SC-19220 and,on Page 140, Lines 11-18, show the chemical structures of the compoundsused in the study.

A. Rakovska et al., "Antagonistic Effect of SC-19220 on the Responses ofGuinea-Pig Gastric Muscles to Prostaglandins E₁, E₂ and F₂," Arch. int.Pharmacodyn, 268, 59-69 (1984), disclose a study of the contractileresponses of guinea-pig gastric muscles to SC-19220, and theprostaglandin-blocking activity and specificity of SC-19220 on thesemuscles.

W. E. Coyne et al., "Anticonvulsant Semicarbazides," J. Med. Chem.,11(6), 1158-1160 1968), disclose the investigation of thestructure-activity relationship of the anticonvulsant activity of aseries of semicarbazides which was synthesized from various tricyclicamines (see Table 1, Page 1160).

K. Gyires et al., "The Use of the Writhing Test in Mice for ScreeningDifferent Types of Analgesics," Arch. int. Pharmacodyn, 267, 131-140(1984), describe a comparison of the analgesic potency of someprostaglandin synthesis inhibitors and morphine using the writhing test.SC-19220 is discussed on Page 133, Lines 10 and 14-16, in Table II (Page134), and on Page 135, Lines 16-25, and Page 137, Lines 34-38.

A. Bennett et al., "Antagonism of Prostanoid-Induced Contractions of RatGastric Fundus Muscle by SC-19220, Sodium Meclofenamate, Indomethacin orTrimethoquinol," Br. J. Pharmac, 71, 169-175 (1980), disclose the studyof the effects of several compounds, including SC-19220, on contractionsof the rat stomach longitudinal muscle to several prostanoids. SC-19220is discussed on Page 175, Paragraph 1, Page 170, Paragraph 4, in Table 1and FIG. 2, on Page 172, Paragraph 2, and on Page 174, Paragraphs 1 and2.

C.A. Maggi et al., "The Effect of SC-19220, a Prostaglandin Antagonist,on the Micturition Reflex in Rats," European Journal of Pharmacology,152, 273-279 (1988), disclose a study in which SC-19220 is said to haveincreased the bladder capacity and reduced the voiding efficiency ofmicturition of urethane-anesthetized rats.

George et al., "Antagonism of Alcohol Hypnosis by Blockade ofProstaglandin Synthesis and Activity: Genotype and Time Course Effects,"Pharmacology Biochemistry & Behavior, 19, 131-136 (1983), disclose astudy of genetic and time-course factors of the effect of the antagonismof alcohol-induced behaviors of mice which have been pretreated withprostaglandin synthetase inhibitors and the effect of SC-19220 onethanol sleep time.

S. Nakajyo et al., "Inhibitory Effect of Bassianolide, ACyclodepsipeptide, on Drug-Induced Contractions of Isolated SmoothMuscle Preparations,"Japan. J. Pharmacol., 32, 55-64 (1982), disclose astudy of the effect of bassianolide on the contractile responses inducedby various types of neurotransmitters and autacoids. SC-19220 wasemployed in this study and is discussed on Page 57, Paragraph 1, inFIGS. 2 and 3, in Table 1, and on Page 60, Paragraph 1, Page 62,Paragraph 3, and Page 63, Paragraph 2.

A. Gomes et al., "Pharmacodynamics of Venom of the Centipede Scolopendrasubspinipes dehaani,"Indian Journal of Experimental Biology, 20, 615-618(1982), disclose an investigation of the pharmacodynamic actions of thevenom of the tropical centipede S. subspinipes. SC-19220 was employed inthis study and is discussed on Page 615 (abstract), Page 616, Line 30,Page 617, Lines 13-18, in FIGS. 4 and 5, and on page 618, Lines 23-26.

Each of the documents described hereinabove discloses compounds whichare structurally different from the compounds of the present invention.Thus, the compounds of the present invention are structurally distinctfrom that which has been described in the art.

Compounds of the present invention have been found to exhibit activityas prostaglandin E₂ antagonists.

SUMMARY OF THE INVENTION

The present invention provides compounds having a structure of FormulaI: ##STR5## or a pharmaceutically-acceptable salt, ester or amidethereof, wherein:

X is oxygen, sulfur, ##STR6##

R¹ is hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, carboxy,alkoxycarbonyl, amino, aminocarbonyl, alkylamino, dialkylamino, amido,halogen, cyano, nitro, trifluoromethyl, sulfonamide, phosphonate, ureaor urethane; and

R² is hydrogen or halogen;

with the proviso that R¹ is not chlorine at position 8 when X is oxygenand R² is hydrogen.

The present invention also provides pharmaceutical compositions whichare pharmaceutically acceptable and which comprise atherapeutically-effective amount of a compound of Formula I incombination with a pharmaceutically-acceptable carrier, and a method foreliminating or ameliorating pain in an animal comprising administering atherapeutically-effective amount of a compound of Formula I to theanimal.

DETAILED DESCRIPTION OF THE INVENTION (1) Definitions

For purposes of clarity, the terms and phrases used throughout thisspecification and the appended claims are defined in the manner setforth directly below.

Some of the chemical structures which are presented in thisspecification and the appended claims have been drawn using theconvention which employs lines to represent alkyl radicals, which isknown by those of skill in the art.

The abbreviations "AcOH" and "HOAc" as used herein mean acetic acid.

The term "alkyl" as used herein means a saturated hydrocarbon radicalhaving from one to ten carbon atoms, and within which includes from oneto six carbon atoms, and further within which includes from one to threecarbon atoms, which can be a straight or branched chain. Representativeof such radicals are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, pentyl and the like.

The term "alkylamino" as used herein means an amino group, as definedbelow, which has one of the hydrogen atoms replaced by an alkyl group,as defined above.

The term "alkoxy" as used herein means an alkyl radical, as definedabove, having an oxygen atom attached thereto. Representative alkoxygroups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term "alkoxycarbonyl" as used herein means an alkoxy group, asdefined above, having a carbonyl group attached thereto, as definedbelow.

The abbreviation "AlMe₃ " as used herein means trimethylaluminum.

The term "amino" as used herein means an --NH₂ group.

The term "aminocarbonyl" as used herein means a carbonyl group, asdefined below, which has an amino group, as defined above, attachedthereto.

The term "amido" as used herein means a ##STR7## group.

The term "analgesia" as used herein means the reduction, or absence, ofsensibility to pain, designating particularly the relief of pain withoutloss of consciousness.

The term "animal" as used herein includes mammals and nonmammals, andfurther includes humans and non-human mammals.

The term "aryl" as used herein means 5- and 6-membered single-ringaromatic radicals which may include from zero to four heteroatoms.Representative aryls include phenyl, thienyl, furanyl, pyridinyl,imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,(is)oxazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridinyl-N-oxide and thelike.

The abbreviation "Boc" as used herein means t-butyloxycarbonyl.

The abbreviation "Calc." as used herein means calculated.

The term "carbonyl" as used herein means a ##STR8## group.

The term "carboxy" as used herein means a ##STR9## group.

The term "composition" as used herein means a product which results fromthe combining of more than one element or ingredient.

The term "cyano" as used herein means a --CN group.

The term "dialkylamino" as used herein means an amino group, as definedabove, which has both of the hydrogen atoms replaced by an alkyl group,as defined above.

The abbreviation "DMAP" as used herein means 4-(dimethylamino)pyridine.

The abbreviation "DMF" as used herein means dimethylformamide.

The abbreviation "DSC" as used herein means Differential ScanningCalorimetry.

The phrase "EC₅₀ concentration" as used herein means that concentrationof a compound or drug which is necessary to elicit a 50% maximalbiological response and, thus, which is necessary to elicit a 50%reduction in the contractions of guinea pig ileum segments in aprostaglandin antagonism assay.

The phrase "ED₅₀ dose" as used herein means that dose of a compound ordrug which produced a biological effect, such as producing analgesia, in50% of the animals to which the compound or drug was administered.

The abbreviation "Et" as used herein means ethyl (--CH₂ CH₃).

The abbreviation "EtOAc" as used herein means ethyl acetate.

The abbreviation "EtOH" as used herein means ethanol (CH₃ CH₂ OH).

The abbreviation "Et₃ N" as used herein means triethylamine.

The term "halo" or "halogen" as used herein means chlorine (Cl), bromine(Br), fluorine (F) and/or iodine (I).

The term "haloalkyl" as used herein means an alkyl radical, as definedabove, which has one or more hydrogen atoms replaced by a halogen atom,as defined above, including, but not limited to, fluoromethyl,2-chloroethyl, trifluoromethyl, 2,2-dichloroethyl and the like.

The term "heteroatom" as used herein means an atom of any element otherthan carbon or hydrogen.

The abbreviation "¹ H NMR" as used herein means Proton Nuclear MagneticResonance.

The abbreviation "HPLC" as used herein means High Pressure LiquidChromatography.

The term "hydroxy" as used herein means the group --OH.

The term "intragastrically" and/or the abbreviation "i.g." as usedherein means that a compound or drug was administered into the stomach.

The abbreviation "i.p." as used herein means that a compound or drug wasadministered intraperitoneally.

The abbreviation "IR" as used herein means infrared, referring to aninfrared spectrum.

The abbreviation "LAH" as used herein means lithium aluminum hydride.

The abbreviation "Me" as used herein means methyl (--CH₃).

The abbreviation "MeOH" as used herein means methanol (CH₃ OH).

The abbreviation "mp" as used herein means melting point.

The abbreviation "MPLC" as used herein means Medium Pressure LiquidChromatography.

The term "nitro" as used herein means an --NO₂ group.

The abbreviation "n-BuLi" as used herein means n-butyl lithium.

The abbreviation "NMR" as used herein means Nuclear Magnetic Resonance.

The abbreviation "n-Pr" as used herein means n-propyl.

The phrases "parenteral administration" and "administered parenterally"as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrase "pharmaceutically acceptable" is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically-acceptable carrier" as used herein means apharmaceutically-acceptable material, composition or vehicle, as defineddirectly above, such as a liquid or solid filler, diluent, excipient,solvent or encapsulating material, involved in carrying or transportinga chemical compound or pharmaceutical agent from one organ, or portionof the body, to another organ, or portion of the body. Some examples ofmaterials which can serve as pharmaceutically-acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

The phrase "pharmaceutically-acceptable salts" as used herein refers tonon-toxic salts of the compounds of the present invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid, or which are prepared by reacting the free acid with asuitable base. Representative salts include the hydrochloride,hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, napsylate, clavulanate and thelike salts, and alkali metal salts, such as sodium and potassium, andalkaline earth salts, such as calcium and magnesium.

The term "phosphonate" as used herein means a ##STR10## group, wherein Yand Z may be the same or different, and may be hydrogen, alkyl or aryl.

The abbreviation "p.o." as used herein means that a compound or drug wasadministered orally.

The phrase "protecting group" as used herein means substituents whichprotect the reactive functional group from undesirable chemicalreactions. Examples of such protecting groups include esters ofcarboxylic acids, ethers of alcohols and acetals and ketals of aldehydesand ketones.

The phrase "N-protecting group" or "N-protected" as used herein meansthose groups intended to protect the N-terminus of an amino acid orpeptide, to protect an amino group against undesirable reactions duringsynthetic procedures and includes, but is not limited to, sulfonyl,acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxy (Cbz),benzoyl and an L- or D-aminoacyl residue, which may itself beN-protected similarly.

The abbreviation "RaNi" as used herein means Raney nickel.

The abbreviation "s.c." as used herein means that a compound or drug wasadministered subcutaneously.

The term "sulfonyl" as used herein means an ##STR11## group.

The term "sulfonamide" as used herein means an ##STR12## group, whereinY is hydrogen, alkyl or aryl, and wherein Z is alkyl or aryl.

The abbreviation "t-Bu" as used herein means tert-butyl.

The abbreviation "TEA" as used herein means triethylamine.

The phrase "therapeutically-effective amount" as used herein means anamount of a compound, material, or composition which is an effectivedose for eliminating or ameliorating pain in an animal, or for producingsome other desired therapeutic effect, at a reasonable benefit/riskratio applicable to any medical treatment.

The abbreviation "THF" as used herein means tetrahydrofuran.

The phrases "title compound," "title product" and "title material" asused herein mean that compound, product or material whose chemical nameis given, and/or whose structure is shown, in the particular example, orsubpart thereof, referred to. If no particular example, or subpartthereof, is referred to, it means that compound, product or materialwhose chemical name is given, and/or whose structure is shown, in theparticular example, or subpart thereof, in which it appears.

The term "trifluoromethyl" as used herein means a --CF₃ group.

The term "urea" as defined herein means an ##STR13## group, wherein eachof W, Y and Z is the same or different, and may be hydrogen, alkyl oraryl.

The term "urethane" as used herein means an ##STR14## group, wherein Yand Z may be the same or different, and may be hydrogen, alkyl or aryl.

(2) Description of Invention

In one aspect, the present invention provides compounds comprising astructure of Formula I, as described above, andpharmaceutically-acceptable salts, esters and amides thereof.

The compounds of the present invention comprise a class of substituteddibenzoxazepine compounds in which the 1, 2, 3, 4, 5, 6, 7, 8 and/or9-position is substituted. Compounds within the present invention havebeen shown to exhibit activity as prostaglandin E₂ antagonists.

Specific compounds within the scope of the invention include, but arenot limited to, the compounds discussed in the examples presented below,as well as their pharmaceutically-acceptable salts, esters, and amides.

Contemplated equivalents of the compounds described in Formula I includecompounds which otherwise correspond thereto, and which have the samegeneral properties thereof, wherein one or more simple variations ofsubstituents are made which do not adversely affect the efficacy of thecompound.

Certain compounds of this invention may exist in geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans- geometric isomers, R- andS-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixturesthereof, and other mixtures thereof, as falling within the scope of theinvention. Additional asymmetric carbon atoms may be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Certain compounds of the present invention may contain a basicfunctional group, such as amino, alkylamino or dialkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term "pharmaceutically-acceptablesalts" in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, for example, S. M. Berge et al., "Pharmaceutical Salts," J. Pharm.Sci., 66, 1-19 (1977), which, as well as all other documents referred toherein, is incorporated herein by reference.)

In other cases, the compounds of the invention may contain one or moreacidic functional groups, such as carboxyl and the like, and, thus, arecapable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable bases. The term "pharmaceutically-acceptablesalts" in these instances refers to the relatively non-toxic, inorganicand organic base addition salts of compounds of the present invention.These salts can likewise be prepared in situ during the final isolationand purification of the compounds, or by separately reacting thepurified compound in its free acid form with a suitable base, such asthe hydroxide, carbonate or bicarbonate of a metal cation, with ammonia,or with a pharmaceutically-acceptable organic primary, secondary ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine and the like. (See, forexample, S.M. Berge et al., "Pharmaceutical Salts," supra.)

In another aspect, the present invention providespharmaceutically-acceptable compositions which comprise atherapeutically-effective amount of one or more of the compounds ofFormula I, as described hereinabove, formulated together with one ormore pharmaceutically-acceptable carriers. The pharmaceuticalcompositions of the invention may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal or vaginal administration.

In yet a further aspect, the present invention provides a method foreliminating or ameliorating pain in an animal, or for producing someother therapeutic effect, as discussed in more detail hereinbelow,comprising administering a therapeutically-effective amount of acompound of Formula I, as described hereinabove, to the animal.

The preferred embodiments of this invention are the compounds describedin Examples 8, 9, 11, 13, 14, 16, 20 and 21 below. The most preferredembodiment of the invention is the compound described in Example 20below.

(3) Utility

Compounds of the present invention exhibit activity as prostaglandin E₂antagonists (prostaglandin antagonists of the E₂ series).

Compounds within the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds, are useful asanalgesic agents for the elimination or amelioration of pain in animals.

In addition to treating pain, these compounds and compositions would beuseful in treating convulsions, ischemia and other central nervoussystem disorders, as well as osteoporosis, dysmenorrhea, asthma,enuresis, arrhythmia, urinary incontinence, gastric hypermotility,irritable bowel syndrome and diarrhea, by virtue of their activity asprostaglandin E₂ antagonists.

(4) Methods of Preparation

In general, the compounds of the present invention may be prepared bythe methods illustrated in the following general reaction schemes, or bymodifications thereof, using readily available starting materials,reagents and conventional synthesis procedures. Unless otherwisespecified, the various substituents of the compounds are defined in thesame manner as they are defined above in Formula I in the "Summary ofInvention" section.

If a particular enantiomer of a compound of the present invention isdesired, it may be prepared by chiral synthesis, or by derivation with achiral auxiliary, where the resulting diastereomeric mixture isseparated and the auxiliary group cleaved to provide the pure desiredenantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

In each of the General Reaction Schemes, urea may be synthesized byreacting the title compound (product) of Example 13 hereinbelow with theappropriate isocyanate, as known by those of skill in the art. Inaddition, urethane may be synthesized by combining theappropriately-substituted chloroformate, which is commerciallyavailable, with the title compound (product) of Example 13. Phosphonatemay be synthesized by making the trifluoromethanesulfonate ester of thetitle compound (product) of Example 19 by standard techniques known bythose of skill in the art, and reacting the resultingtrifluoromethanesulfonate ester with a dialkylphosphite and palladium(0). The result is a phosphonate ester. One of ordinary skill in the artknows how to synthesize the various possible substitutions of the urea,urethane, phosphonate, as well as sulfonamide, which are discussed inthe definition section of this specification, where each of these termsis defined.

In General Reaction Scheme No. 1, substituted salicaldehyde orthiosalicaldehyde (wherein X is oxygen or sulfur and wherein R² ishydrogen or halogen) is reacted with base, and to this is addedsubstituted 2-chloronitrobenzene (wherein R¹ is hydrogen, hydroxy,alkyl, haloalkyl, alkoxy, carboxy, alkoxycarbonyl, amino, aminocarbonyl,alkylamino, dialkylamino, amido, halogen, cyano, nitro, trifluromethyl,sulfonamide, phosphonate, urea or urethane). The resulting ether (orthioether) is reduced to yield substituted dibenzoxazepine(dibenzothiazepine), wherein R¹ and R² are as described hereinabove. Thenitrogen is functionalized to yield a diacylhydrazide. Ifdibenzothiazepine, oxidation of the sulfur is achieved with hydrogenperoxide.

In General Reaction Scheme No. 2, substituted salicaldehyde orthiosalicaldehyde (wherein X is oxygen or sulfur and wherein R² ishydrogen or halogen) is reacted with substituted 2-chloroaniline(wherein R¹ is as described in General Reaction Scheme No. 1). Theresulting imine is reacted with base to form a tricycle. The resultingimine is reduced with NABH₃ CN to yield substituted dibenzoxazepine(dibenzothiazepine), wherein R¹ and R² are as described hereinabove. Thenitrogen is functionalized to yield a diacylhydrazide. Ifdibenzothiazepine, oxidation of the sulfur is achieved with hydrogenperoxide.

In General Reaction Scheme no. 3, substituted phenol or thiophenol(wherein X is oxygen or sulfur and wherein R² is hydrogen or halogen) isreacted with base, and to this is added substituted 2-chloronitrobenzene(wherein R₁ is as described in General Reaction Scheme No. 1). Theresulting ether (or thioether) is reduced to yield an amine. The amineis reacted with phosgene followed by aluminum chloride. The resultinglactam is reduced with lithium aluminum hydride. The nitrogen isfunctionalized to yield a diacylhydrazide, Wherein R¹ and R² are asdescribed hereinabove. If dibenzothiazepine, oxidation of the sulfur isachieved with hydrogen peroxide.

In each of the three general reaction schemes, X represents oxygen orsulfur, each of which is commercially available. ##STR15##

The conditions for carrying out the individual steps in each of thegeneral reaction schemes presented above are conventional, well-known,and capable of wide variation.

Other methods known in the art can also be used to synthesize thecompounds of the present invention.

(5) Dosage and Mode of Administration

The compounds of the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds in combinationwith a pharmaceutically-acceptable carrier, are useful in treating painin animals. A physician or veterinarian of ordinary skill in the art canreadily determine whether or not a patient is in pain.

The pharmaceutical compositions of the present invention, which willtypically comprise one or more of the compounds of Formula I as anactive ingredient in admixture with one or morepharmaceutically-acceptable carriers and, optionally, with one or moreother compounds, drugs or materials, are employed therapeutically and,thus, would generally be used under the guidance of a physician. Theappropriate dosage and form of administration of these compositions willbe suitably selected by methods which are consistent with conventionalpharmaceutical practices.

The pharmaceutical compositions of the present invention may bespecially formulated for oral administration in solid or liquid form,for parenteral injection, and/or for rectal or vaginal administration.They may be administered to humans and other animals for therapy by anysuitable route of administration, including orally, nasally, as by, forexample, a spray, rectally, intravaginally, parenterally,intracisternally and topically, as by powders, ointments or drops,including buccally and sublingually. While the preferred routes ofadministration are orally and parenterally, the most preferred mode ofadministration is orally.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the severity of the pain, theduration of the treatment, other drugs, compounds and/or materials usedin combination with the particular compound employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required to alleviate or ameliorate a particular patient'spain. For example, the physician or veterinarian could start doses ofthe compound of the invention employed in the pharmaceutical compositionat levels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, dosage levels in therange of from about 0.001 mg to about 10 g, more preferably from about 1mg to about 1000 mg, of active compound per kilogram of body weight perday are administered to a mammalian patient. However, the total dailyusage of the compounds of Formula I, or the pharmaceutical compositionscomprising such compounds, will be determined by an attending physicianor veterinarian within the scope of sound medical judgement.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The pharmaceutical compositions of the present invention comprise acompound of the present invention together with one or morepharmaceutically-acceptable carriers thereof and, optionally, with othertherapeutic agents. Each carrier must be "acceptable" in the sense ofbeing compatible with the other ingredients of the formulation and notinjurious to the patient.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfite, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,alpha-tocopherol, and the like; and (3) metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient (compoundof Formula I) which can be combined with a carrier material to produce asingle dosage form will vary depending upon the host being treated, theparticular mode of administration and all of the other factors describedabove. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound which is the lowest dose effective to produce atherapeutic effect. Generally, out of one hundred per cent, this amountwill range from about 1 per cent to about ninety-nine percent of activeingredient, preferably from about 5 per cent to about 70 per cent, mostpreferably from about 10 per cent to about 30 per cent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, with one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient (compound of Formula I) is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, for example, cetylalcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient (compound of Formula I as described above), the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, oliveand sesame oils), glycerol, tetrahydrofuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the invention to the body. Such dosage formscan be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Opthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer, and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissue.

The injectable materials can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or in other sterile injectable mediumsjust prior to use.

The formulations may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in alyophilized condition requiring only the addition of the sterile liquidcarrier, for example water for injections, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the type described above.

The pharmaceutical compositions of the present invention may also beused in the form of veterinary formulations, including those adapted forthe following: (1) oral administration, for example, drenches (aqueousor non-aqueous solutions or suspensions), tablets, boluses, powders,granules or pellets for admixture with feed stuffs, pastes forapplication to the tongue; (2) parenteral administration, for example,by subcutaneous, intramuscular or intravenous injection as, for example,a sterile solution or suspension or, when appropriate, by intramammaryinjection where a suspension or solution is introduced into the udder ofthe animal via its teat; (3) topical application, for example, as acream, ointment or spray applied to the skin; or (4) intravaginally, forexample, as a pessary, cream or foam.

While the various aspects of the present invention are described hereinwith some particularity, those of skill in the art will recognizenumerous modifications and variations which remain within the spirit ofthe invention. These modifications and variations are within the scopeof the invention as described and claimed herein.

(6) Examples

The following examples describe and illustrate the methods for thepreparation of the compounds of the present invention, as well as otheraspects of the present invention, and the results achieved thereby, infurther detail. Both an explanation of, and the actual procedures for,the various aspects of the present invention are described whereappropriate. These examples are intended to be merely illustrative ofthe present invention, and not limiting thereof in either scope orspirit. Those of skill in the art will readily understand that knownvariations of the conditions and processes of the preparative proceduresdescribed in these examples can be used to prepare the compounds of thepresent invention, and the pharmaceutical compositions comprising suchcompounds.

In the examples, all parts are by weight unless otherwise indicated.

All equipment employed in the examples is commercially available. Unlessotherwise indicated, all starting materials employed in the examples arecommercially available. Sources for these materials include SigmaChemical Co. (St. Louis, Mo.), Aldrich Chemical Co. (Milwaukee, Wis.),Lancaster Synthesis (Windham, N.H.), Fisher Scientific (Pittsburgh,Pa.), Boehringer Mannheim Biochemicals (Indianapolis, Ind.), FlukaChemical Corp. (Ronkonkoma, N.Y.) and Chemical Dynamics Corp. (SouthPlainfield, N.J.). Most of the starting materials were obtained fromAldrich Chemical Co. (Milwaukee, Wis.).

All patents and publications referred to in the examples, and throughoutthe specification, are hereby incorporated herein by reference, withoutadmission that such is prior art.

EXAMPLE 1 Dibenz[b,f][1,4]oxazepine-8,10(11 H)-dicarboxylic acid,8-methyl ester, 10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide]##STR16## (a) Methyl 4-(2-formylphenoxy)-3-nitrobenzoate

Sodium hydride (3.09 g) was added in portions to a stirred solution ofsalicylaldehyde (14.3 g) in N,N-dimethylformamide (180 mL) undernitrogen. To the resulting dark solution was added methyl4-chloro-3-nitrobenzoate (23.0 g) and N,N-dimethylformamide (50 mL), andthe reaction was heated at 103° C. for 2.75 hours. The reaction wasevaporated under vacuum, and the resulting oily mixture was partitionedbetween chloroform and water. The layers were separated, and thechloroform layer was washed with 1 M NaOH, water, and brine, dried overmagnesium sulfate, and evaporated under vacuum to a yellow solid.Recrystalization from methanol yielded the title compound as lightyellow crystals Mp: 109°-110° C.

b) Methyl 10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylate

The title compound of Example 1(a) (17 g) in tetrahydrofuran (150 mL)was shaken in a Parr hydrogenator at 5 psi hydrogen with Raney nickel atroom temperature for 4 hours. The catalyst was filtered from thereaction, and the solution was evaporated under vacuum to an oil whichcrystallized on standing. Recrystallization from methanol yielded thetitle compound as white needles. Mp: 125°-126° C.

(c) Dibenz[b,f][1,4]oxazepine-8,10(11 H)-dicarboxylic acid, 8-methylester, 10-[2-[3-(ethylsulfonyl)-1-oxopropyl]-hydrazide]

Methyl 3-(ethylsulfonyl)propanoate was prepared in the manner describedin "Sulfinic Acids. I.," Chemical Abstracts, 51(F03), 1064 (1956). Theaddition of sulfinic acids to an α,β-unsaturated compound (esters,ketones, amides, nitriles) results in sulfones. The reaction isconducted in an aqueous solution in the presence of NaH₂ PO₄ (0.11 moleper 0.1 mole of Na salt of the sulfinic acid and 0.12 mole of theα,β-unsaturated compound in 200 mL of water).

To a stirring solution of methyl 3-(ethylsulfonyl)propanoate (10 mmol)in ethanol (30 mL) was added hydrazine monohydrate (15 mmol), and theresulting solution was stirred for 16 hours. The resulting precipitatewas collected to yield 2-[3-(ethylsulfonyl)-1-oxopropyl], hydrazide as awhite solid (52%).

To a stirred solution of phosgene (1.93 M in toluene, 9.3 mL) intetrahydrofuran (45 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example1(b) (2.5 g) and triethylamine (1.5 mL) in tetrahydrofuran (30 mL). Theice bath was removed, and the reaction was stirred at ambienttemperature for 1.5 hours. The reaction was then evaporated undervacuum, and to the resulting residue was added2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (1.76 g), triethylamine (1.5mL) and toluene (50 mL). The reaction mixture was refluxed for 2 hoursand cooled to room temperature. The precipitate was collected byfiltration, washed with ether, suspended in water, and heated on a steambath for 5 minutes. After cooling to room temperature, the insolubleproduct was collected by filtration and crystallized from methanol.Recrystallization from methanol yielded the pure title compound as awhite solid. Mp: 172°-176° C.

EXAMPLE 2 Dibenz[b,f][1,4]oxazepine-7,10(11 H)-dicarboxylic acid,7-methyl ester, 10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide]##STR17##

The title compound was prepared by the method described above for thepreparation of the title compound of Example 1, with the exception thatmethyl 10,11-dihydrodibenz[b,f]oxazepine-7-carboxylate was employed inplace of the title compound of Example 1(b).

EXAMPLE 3 Dibenz[b,f][1,4]oxazepine-8,10(11 H)-dicarboxylic acid,8-(1,1-dimethylethyl) ester,10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide] ##STR18## (a)1,1-dimethylethyl 4-chloro-3-nitrobenzoate

A solution of n-butyl lithium (1.6 M, 101 mL) was added dropwise tostirring anhydrous tert-butanol (200 mL) under nitrogen in a roomtemperature water bath. After 0.5 hours, 4-chloro-3-nitrobenzoylchloride (10.0 g) was added, and the dark solution was stirred for 1.5hours at room temperature. The reaction was evaporated under vacuum, andthe residue was crystallized from hexane to yield the title compound asan orange solid. Mp: 66°-67° C.

(b) 1,1-dimethylethyl 4-(2-formylphenoxy)-3-nitrobenzoate

Sodium hydride (0.79 g) was added in portions to a stirred solution ofsalicylaldehyde (3.83 g) in N,N-dimethylformamide (60 mL) undernitrogen. To the resulting dark solution was added the title compound ofExample 3(a) (7.0 g), and the reaction was stirred at 100° C. for 2.5hours. The reaction was evaporated under vacuum, and the residue waspartitioned between chloroform and 1 M NaOH. The layers were separated,and the aqueous layer was extracted once more with chloroform. Thecombined chloroform extracts were washed with 1 M NaOH, water and brine,dried over magnesium sulfate, and evaporated under vacuum to a dark oil.Flash chromatography through silica gel 60 using 2:1 chloroform:hexaneyielded the title compound as a thick, yellow oil.

(c) 1,1-dimethylethyl10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylate

The title compound of Example 3(b) (4.8 g) in tetrahydrofuran (160 mL)was shaken in a Parr hydrogenator at 30 psi hydrogen with Raney nickelat room temperature for 4 hours. The catalyst was filtered from thereaction, and the solution was evaporated under vacuum. Flashchromatography through silica gel 60 using 9:1 hexane:ethyl acetateyielded the title compound as a yellow solid. Mp: 121°-123° C.

(d) Dibenz[b,f][1,4]oxazepine-8,10(11 H)-dicarboxylic acid,8-(1,1-dimethylethyl) ester. 10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide]

To a stirred solution of phosgene (1.93 M in toluene, 6.7 mL) intetrahydrofuran (30 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example3(c) (2.0 g) and triethylamine (1.0 mL) in tetrahydrofuran (20 mL). Theice bath was removed, and the reaction was stirred at ambienttemperature for hour. The reaction was evaporated under vacuum, and tothe resulting residue was added2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (1.22 g), triethylamine (1.0mL) and toluene (40 mL). The resulting mixture was refluxed for 2.5hours, and evaporated under vacuum. The residue was partitioned betweenchloroform and water, the layers were separated, and the chloroformlayer was washed with water, saturated sodium bicarbonate, and brine.After drying over magnesium sulfate, the solution was evaporated undervacuum. The crude product was flash chromatographed through silica gel60 using 3:1 chloroform:tetrahydrofuran to yield a thick oil. The oilwas placed under vacuum at room temperature to yield the title compoundas a solidified white foam. HPLC: 99.66% pure.

EXAMPLE 4 Dibenz[b,f][1,4]oxazepine-8,10(11 H)-dicarboxylic acid,10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide] ##STR19##

A solution of the title compound of Example 3(d) (2.05 g), HCl (6.9 M indioxane, 35 mL), and glacial acetic acid (35 mL) were stirred togetherat room temperature for 2.5 hours. The reaction was evaporated undervacuum, pentane was added, and the mixture was again evaporated undervacuum. The residue was dissolved in a minimal amount of tetrahydrofuranand treated with pentane to force the product out of solution. Themixture was evaporated under vacuum, and the semi-solid residue waschromatographed through a medium pressure liquid chromatography columnpacked with acidic silica gel, using tetrahydrofuran. Aftercrystallization from tetrahydrofuran/pentane, the yellowish product waswashed with tetrahydrofuran, hexane and then ether to yield the titlecompound as a white solid. Mp: 191°-194° C.

EXAMPLE 5 Dibenz[b,f][1,4]oxazepine-7,10(11 H)-dicarboxylic acid,1,1-(dimethylethyl) ester,10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide] ##STR20##

The title compound was prepared by the method described above for thepreparation of the title compound of Example 3, with the exception that3-chloro-4-nitrobenzoyl chloride was employed in place of4-chloro-3-nitrobenzoyl chloride as the starting material.

EXAMPLE 6 Dibenz[b,f][1,4]oxazepine-7,10(11 H)-dicarboxylic acid,10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide] ##STR21##

The title compound was prepared by the method described above for thepreparation of the title compound of Example 4, with the exception thatdibenz[b,f][1,4]oxazepine-7,10(11 H)-dicarboxylic acid,7(1,1-dimethylethyl) ether,10-[2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide] was employed in place ofthe title compound of Example 3(d) as the starting material.

EXAMPLE 7 8-fluorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR22## (a)2-(4-fluoro-2-nitrophenoxy)benzaldehyde

Sodium hydride (1.66 g) was added in portions to a stirred solution ofsalicylaldehyde (8.06 g) in N,N-dimethylformamide (100 mL) undernitrogen. To the resulting yellow solution was added2,5-difluoro-1-nitrobenzene (10.0 g) and N,N-dimethylformamide (10 mL).The reaction was heated at 50° C. for 18 hours and evaporated undervacuum. The oily mixture was taken up in chloroform, and washed with 1 MNaOH, water, 1 M HCl, and brine, dried over magnesium sulfate, andevaporated under vacuum to an orange oil. The oil was treated with ethylether, cooled in an ice bath, and the precipitated product was collectedby filtration to yield the title compound as white crystals. Mp: 94°-95°C.

(b) 8-fluoro-10,11-dihydrodibenz[b,f][1,4]oxazepine

The title compound of Example 7(a) (5.0 g) in 1:1 methanol:ethyl acetate(200 mL) was shaken in a Parr Hydrogenator at 30 psi hydrogen with Raneynickel at room temperature for 13.75 hours. The catalyst was filteredfrom the reaction, and the solution was evaporated under vacuum. Theresidue was flash chromatographed through silica gel 60 using chloroformto yield the title compound as a white solid. Mp: 94° C.

(c) 8-fluorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a stirred solution of phosgene (1.93 M in toluene, 93 mL) intetrahydrofuran (40 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example7(b) (2.0 g) and triethylamine (1.4 mL) in tetrahydrofuran (30 mL). Theice bath was removed, and the reaction was stirred at ambienttemperature for 1 hour. The reaction was evaporated under vacuum, and tothe residue was added 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (1.68g), triethylamine (1.4 mL) and toluene (55 mL). The reaction mixture wasrefluxed under nitrogen for 3 hours, and stirred at room temperatureovernight. The mixture was evaporated under vacuum, and the residue wasstirred with a mixture of chloroform (125 mL) and 1 M HCl (125 mL). Thebi-phasic mixture was filtered to collect the undissolved product. Thechloroform layer was washed with brine, dried over magnesium sulfate,and evaporated under vacuum. This was combined with the undissolvedproduct collected previously, washed with ethyl ether, and crystallizedfrom ethanol (3A) to yield the title compound as a white solid. Mp:191°-193° C.

EXAMPLE 8 2-chlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR23## (a)5-chloro-2-(2-nitrophenoxy)benzaldehyde

To a stirred solution of 5-chlorosalicylaldehyde (4.00 g) inN,N-dimethylformamide (40 mL) under nitrogen was added sodium hydride inportions (0.64 g). To the resulting reddish solution was added asolution of 1-fluoro-2-nitrobenzene (3.50 g) in N,N-dimethylformamide(10 mL) in one lot. The reaction was then stirred at 63° C. undernitrogen for 24 hours. The reaction was evaporated under vacuum, and theresidue was partitioned between chloroform and 1 N NaOH. The layers wereseparated, and the aqueous layer was extracted once more withchloroform. The combined chloroform extracts were washed with 1 N NaOH,water, 1 N HCl, water, and brine, dried over magnesium sulfate, andevaporated under vacuum. The residue was crystallized from cyclohexaneto yield the title compound as a light yellow solid. Mp: 103°-105° C.

(b) 2-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine

A solution of the title compound of Example 8(a) (2.00 g) intetrahydrofuran (100 mL) was shaken over Raney Nickel in a ParrHydrogenator at 5 psi hydrogen. The catalyst was removed by filtration,and the filtrate was evaporated under vacuum. Flash chromatography on amedium pressure liquid chromatography system through silica gel 60 using2:1 chloroform:hexane yielded the desired title compound as a yellowsolid. Mp: 123°-125° C.

(c) 2-chlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a cold (ice water bath) solution of phosgene (1.93 M in toluene, 3.5mL) and tetrahydrofuran (15 mL) under nitrogen was added dropwise asolution of the title compound of Example 8(b) (0.75 g) andtriethylamine (0.53 mL) in tetrahydrofuran (12 mL). The resultingmixture was stirred for 90 minutes at room temperature, and the reactionwas evaporated under vacuum. To the residue was added2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (0.61 g), triethylamine (0.53mL) and toluene (20 mL), and the reaction was refluxed under nitrogenfor 3.5 hours, and then stirred at room temperature overnight. Thereaction mixture was diluted with ethyl ether, and the solid wascollected by filtration. The solid was washed with ethyl ether, and wassuspended in water (25 mL). After heating on a steam bath for 5 minutes,the undissolved product was collected by filtration, washed with waterfollowed by ethyl ether, and air dried. Flash chromatography throughsilica gel 60 using 3:1 chloroform: tetrahydrofuran followed bycrystallization from ethanol (3A) yielded the desired title compound asa white solid. Mp: 184°-185° C.

EXAMPLE 9 2.8-dichlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylicacid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR24## (a)5-chloro-2-(4-chloro-2-nitrophenoxy)benzaldehyde

To a stirred solution of 5-chlorosalicylaldehyde (8.56 g) inN,N-dimethylformamide (90 mL) under nitrogen was added, in portions,sodium hydride (1.37 g). To the resulting solution was added2,5-dichloro-1-nitrobenzene (10.0 g) and N,N-dimethylformamide (10 mL),and the reaction was heated at 100° C. under nitrogen for 6 hours. Thereaction was evaporated under vacuum, and the residue was partitionedbetween chloroform and 1 N NaOH. The layers were separated, and theaqueous layer was extracted once more with chloroform. The combinedchloroform extracts were washed with 1 N NaOH, water, 1 N HCl, water,and brine, dried over magnesium sulfate, and evaporated under vacuum.Crystallization from methanol yielded the title compound as a yellowsolid. Mp: 128°-130° C.

(b) 2.8-dichloro-10,11-dihydrodibenz[b,f][1,4]-oxazepine

A solution of the title compound of Example 9(a) (2.00 g) intetrahydrofuran (100 mL) was shaken over Raney Nickel in a ParrHydrogenator at 5 psi hydrogen. The catalyst was removed by filtration,and the filtrate was evaporated under vacuum. Flash chromatography on amedium pressure liquid chromatography system through silica gel 60 using1:1 chloroform:hexane yielded the desired title compound as a yellowsolid. Mp: 103°-105° C.

(c) 2,8-dichlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a cold (ice water bath) solution of phosgene (1.93 M in toluene, 1.2mL) and tetrahydrofuran (6 mL) under nitrogen was added dropwise asolution of the title compound of Example 9(b) (0.28 g) andtriethylamine (0.18 mL) in tetrahydrofuran (4 mL). The resulting mixturewas stirred for 30 minutes at room temperature, and then refluxed on asteam bath for 1 hour. The reaction was evaporated under vacuum, and tothe residue was added 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (0.21g), triethylamine (0.18 mL) and toluene (7 mL), and the reaction wasrefluxed under nitrogen for 3 hours, and then stirred at roomtemperature overnight. The reaction mixture was diluted with ethylether, and the solid was collected by filtration. The solid was washedwith ethyl ether followed by 1 N HCl, and then again with ethyl ether.This was flash chromatographed through silica gel 60 using 95:5chloroform:methanol. The resulting residue was triturated with ethanol(3A), diluted with isopropyl ether, and the solid was collected byfiltration to yield the title compound as a white solid. Mp: 189°-190°C.

EXAMPLE 10 8-nitrodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR25## (a)2-[[(2-chloro-5-nitrophenyl)imino]methyl]phenol

A solution of salicylaldehyde (30.0 g) and 2-chloro -5-nitroanaline(42.5 g) in ethanol (3A, 600 mL) was heated at reflux for 3 hours. Theresulting mixture was cooled to 0° C. for one hour, and the product wascollected by filtration, washed with cold ethanol followed by hexane,and air dried to yield the title compound as orange crystals. Mp:168°-169° C.

(b) 8-nitrodibenz[b,f][1,4]oxazepine

Sodium hydride (5.71 g) was added in portions to a stirred solution ofthe title compound of Example 10(a) (59.3 g) in N,N-dimethylformamide(550 mL) under nitrogen at 53° C. After stirring for 2 hours at 53° C.,the resulting mixture was evaporated under vacuum to a volume ofapproximately 150 mL, and water (1 L) was added. The precipitatedproduct was collected by filtration and rinsed twice with water. Thewet, crude product was taken up in hot ethyl acetate, dried overmagnesium sulfate while hot, filtered, and allowed to cool. Thecrystallized product was collected by filtration and washed with coldethanol (3A) followed by hexane to yield the title compound as a tansolid. Mp: 179°-181° C.

(c) 10,11-dihydro-8-nitrodibenz[b,f][1,4]oxazepine

To a stirred mixture of the title compound of Example 10(b) (24.0 g) andsodium cyanoborohydride (6.72 g) in absolute ethanol (480 mL) was addedconcentrated hydrochloric acid until a pH of 4 was achieved. Thereaction was stirred at room temperature for 2.5 hours, addingconcentrated hydrochloric acid as necessary to maintain the pH between3.5 and 4.0. The reaction was evaporated under vacuum to remove abouttwo thirds of the volume, and was then poured into saturated sodiumbicarbonate. The resulting mixture was extracted with chloroform, andthe chloroform extract was washed with saturated sodium bicarbonate andbrine, dried over magnesium sulfate, and evaporated under vacuum.Recrystallization from toluene yielded the title compound as orangecrystals. Mp: 154°-156° C.

(d) 8-nitrodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a stirred solution of phosgene (1.93 M in toluene, 15.6 mL) intetrahydrofuran (65 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example10(c) (4.0 g) and triethylamine (2.4 mL) in tetrahydrofuran (40 mL). Theice bath was removed, and the reaction was stirred at ambienttemperature for 1.5 hours. The reaction was evaporated under vacuum, andto the residue was added 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (3.0g), triethylamine (2.4 mL) and toluene (80 mL). The reaction mixture wasrefluxed for 2 hours, cooled to room temperature, diluted with ether,and the precipitate was collected by filtration. After washing withether, the precipitate was suspended in water, heated on a steam bathfor 5 minutes, and cooled to room temperature. The insoluble product wascollected by filtration, washed with water followed by ether, andrecrystallized from ethanol (3A) to yield the title compound as whiteneedles. Mp: 198°-200° C.

EXAMPLE 11 8-cyanodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,

2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR26##

(a) 4-chloro-3-[[(2-hydroxyphenyl)-methylene]amino]benzonitrile

A solution of salicylaldehyde (4.80 g) and 2-chloro-5-cyanoanaline (6.0g) in ethanol (3A, 150 mL) was heated at reflux for 3 hours. Theresulting mixture was cooled to room temperature overnight, and theproduct was collected by filtration, washed with cold ethanol, and airdried to yield the title compound as a yellow solid. Mp: 147°-148° C.

(b) Dibenz[b,f][1,4]oxazepine-8-carbonitrile

Sodium hydride (0.47 g) was added in portions to a stirred solution ofthe title compound of Example 11(a) (4.50 g), and a catalytic amount ofcopper powder in N,N-dimethylformamide (50 mL) under nitrogen. Thereaction was heated to 100° C. and stirred for 3 hours. The resultingmixture was evaporated under vacuum and partitioned between chloroformand water. The layers were separated, and the water layer was extractedonce more with chloroform. The combined chloroform extracts were washedwith water and brine, dried over magnesium sulfate, and evaporated undervacuum to a brown solid. Recrystallization from ethanol (3A) yielded thetitle compound as yellow needles. Mp: 158°-159° C.

(c) 10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carbonitrile

To a stirred mixture of the title compound of Example 11(b) (1.60 g) andsodium cyanoborohydride (0.49 g) in absolute ethanol (35 mL) was addedconcentrated hydrochloric acid until a pH of 4 was achieved. Thereaction was stirred at room temperature for 2.5 hours, addingconcentrated hydrochloric acid as necessary to maintain the pH between3.5 and 4.0. The reaction was evaporated under vacuum, and the residuewas partitioned between saturated sodium bicarbonate and chloroform. Thelayers were separated and the chloroform layer was washed with saturatedsodium bicarbonate, water, and brine, dried over magnesium sulfate, andevaporated under vacuum to a yellow solid. Flash chromatography throughsilica gel 60 using chloroform yielded the title compound as a whitesolid. Mp: 104°-105° C.

(d) 8-cyanodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a stirred solution of phosgene (1.93 M in toluene, 4.3 mL) intetrahydrofuran (18 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example11(c) (1.0 g) and triethylamine (0.65 mL) in tetrahydrofuran (1I mL).The ice bath was removed, and the reaction was stirred at ambienttemperature for one hour. The reaction was evaporated under vacuum, andto the residue was added 2-[3-(ethylsulfonyl)-1 -oxopropyl]hydrazide(0.82 g), triethylamine (0.65 mL) and toluene (22 mL). The reactionmixture was refluxed for 2 hours, cooled to room temperature, dilutedwith ether, and the precipitate was collected by filtration. Afterwashing with ether, the precipitate was suspended in water, heated on asteam bath for 5 minutes, and cooled to room temperature. The insolubleproduct was collected by filtration, washed with water followed byether, and recrystallized from ethanol (3A) to yield the title compoundas white needles. Mp: 188°-190° C.

EXAMPLE 12 6-chlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR27## (a)2-[[(2,3-dichlorophenyl)imino]methyl]phenol

Salicylaldehyde (11.31 g) and 2,3-dichloroanaline (15.00 g) wererefluxed in absolute ethanol (100 mL) under nitrogen for 3 hours. Thereaction was cooled to room temperature, and the precipitated productwas collected by filtration, washed with ethanol, and pressed to removeas much solvent as possible. The product was dried under vacuum at 56°C. to produce the title compound as a yellow solid. Mp: 89°-90° C.

(b) 6-chlorodibenz[b,f][1,4]oxazepine

To a stirred solution of the title compound of Example 12(a) (5.00 g) inN,N-dimethylformamide (50 mL) under nitrogen was added in portionssodium hydride (0.50 g), a catalytic amount of copper powder, andN,N-dimethylformamide (50 mL). The reaction was stirred at 100° C. undernitrogen for 3 hours, and then at 150° C. overnight. The reaction wasevaporated under vacuum, and the residue was partitioned betweenchloroform and water. The layers were separated, and the aqueous layerwas extracted once more with chloroform. The combined chloroformextracts were washed with water and brine, dried over magnesium sulfate,and evaporated under vacuum to a dark red oil. Flash chromatographythrough silica gel 60 using chloroform yielded the title compound as athick, yellow oil.

(c) 6-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine

To a stirred mixture of the title compound of Example 12(b) (2.00 g) andsodium cyanoborohydride (0.59 g) in absolute ethanol (40 mL) was addedconcentrated hydrochloric acid until a pH of 4 was achieved. Thereaction was stirred at room temperature for 4 hours adding concentratedhydrochloric acid as necessary to maintain the pH between 3 and 4. Thereaction was evaporated under vacuum, and the residue was partitionedbetween saturated sodium bicarbonate and chloroform. The layers wereseparated, and the aqueous layer was extracted once more withchloroform. The combined chloroform extracts were washed with saturatedsodium bicarbonate, water, and brine, dried over magnesium sulfate, andevaporated under vacuum. Flash chromatography through silica gel 60using 4:1 chloroform:hexane yielded the title compound as a yellow oil.

(d) 6-chlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a stirred solution of phosgene (1.93 M in toluene, 6.5 mL) intetrahydrofuran (30 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example12(c) (1.50 g) and triethylamine (1.0 mL) in tetrahydrofuran (20 mL).The ice bath was removed, and the reaction was stirred at ambienttemperature for 2 hours. The reaction was evaporated under vacuum, andto the residue was added 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide(1.28 g), triethylamine (1.0 mL) and toluene (35 mL). The reactionmixture was refluxed for 2.5 hours, cooled to room temperature, dilutedwith ether, and the precipitate was collected by filtration. Afterwashing with ether, the precipitate was suspended in water, heated on asteam bath for 5 minutes, and cooled to room temperature. The insolubleproduct was collected by filtration and washed with water followed byether. Chromatography yielded the desired title compound as a whitesolid. Mp: 209°-211° C.

EXAMPLE 13 8-aminodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR28##

A solution of the title compound of Example 10 (4.0 g) intetrahydrofuran (250 mL) was shaken in a Parr Hydrogenator at 38 psihydrogen over 5% palladium on carbon for 18 hours. The catalyst wasfiltered from the reaction, and the solution was evaporated undervacuum. Crystallization of the residue from ethanol (3A) yielded thetitle compound as a yellow solid. Recrystallization of this from ethanol(3A) yielded the pure title compound as yellow crystals. Mp: 172°-179°C.

EXAMPLE 14 8-[(methylsulfonyl)amino]dibenz[b,f][1,4]-oxazepine -10(11H)-carboxylic acid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR29##

To a stirred solution of the title compound of Example 13 (1.0 g) inpyridine (15 mL) under nitrogen at approximately 5° C. (ice water bath)was added dropwise via syringe methanesulfonyl chloride (0.28 mL). Theice bath was removed, and the reaction was stirred at ambienttemperature for 2 hours. The reaction was then evaporated under vacuum,and the residue was treated with 1 M HCl. The insoluble product wascollected by filtration, washed twice with 1 M HCl, and then with water.The solid was suspended in methanol, heated to reflux on a steam bath,cooled to room temperature, and the product was collected by filtration.Recrystallization from acetonitrile yielded the title compound as apinkish solid. Mp: 211°-212° C.

EXAMPLE 15 8-(diethylamino)dibenz[b,f][1,4]oxazepine-10(11 H)-carboxylicacid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR30##

To a stirred solution of the title compound of Example 13 (2.0 g),acetaldehyde (3.0 mL), sodium cyanoborohydride (0.904 g), and water (2.6mL) in acetonitrile (20 mL) was added glacial acetic acid (0.5 mL) overa period of 6 minutes. The reaction was stirred for 2.5 hours at ambienttemperature, and then glacial acetic acid was added (0.5 mL), and thereaction was stirred for an additional 30 minutes. The resulting mixturewas evaporated under vacuum, and the residue was partitioned betweenethyl acetate and saturated sodium bicarbonate. The layers wereseparated, and the aqueous layer was extracted once more with ethylacetate. The combined ethyl acetate extracts were washed with brine,dried over magnesium sulfate, and evaporated under vacuum to a clear,greenish oil. The oil was chromatographed four times:twice throughsilica gel 60 using 97:3 ethyl acetate:ethanol; next through silica gel60 using 3:1 chloroform:tetrahydrofuran; and finally through reversephase silica gel (C18) using 80:20:1 acetonitrile:water:ammoniumhydroxide. The product from the last column was co-evaporated threetimes with ethanol to azeotrope water from the product and dried undervacuum at room temperature to yield the title compound as a white solidcontaining 1.86% water. HPLC: 99.53% pure.

EXAMPLE 16 8-methoxydibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR31## (a)4-methoxy-2-nitro-1-phenoxybenzene

Sodium hydride (2.30 g) was added in portions to a solution of phenol(8.23 g) in N,N-dimethyl formamide (100 mL) in a room temperature waterbath under nitrogen. The water bath was removed, and to the darksolution was added copper powder (0.74 g), 4-bromo-3-nitroanisole (13.54g) and N,N-dimethylformamide (25 mL). The mixture was heated to 125° C.for 3 hours, and then evaporated under vacuum. The residue waspartitioned between ether and 1 M NaOH and filtered through celite. Thebiphasic filtrate was separated, and the ethereal layer was washed with1 N NaOH, water, and brine, dried over magnesium sulfate, and evaporatedunder vacuum. The crude oil was distilled under vacuum, and a fractionboiling at 155° C. (0.1 mm Hg) was collected. The impure fractions werecombined with the pot residue and flash chromatographed through silicagel 60 using 4:1 chloroform:hexane. The distilled product andchromatographed product were combined to yield the title compound as anorange oil.

(b) 5-methoxy-2-phenoxybenzeneamine

A solution of the title compound of Example 16(a) (8 g) in methanol (70mL) was shaken in a Parr Hydrogenator over 5% palladium on carbon at 5psi hydrogen at room temperature for 6.75 hours. The catalyst wasfiltered from the reaction, and the solution was evaporated undervacuum. Flash chromatography through silica gel 60 using chloroformyielded the title compound as a yellow solid. Mp: 112°-114° C.

(c) 8-methoxydinenz[b,f][1,4]oxazepin-11(10H)-one

To a solution of phosgene (1.93 M in toluene, 60 mL) in toluene (90 mL)under nitrogen at approximately 5° C. was added, in portions, the titlecompound of Example 16(b) (5.0 g). The resulting solution was stirred at0°-5° C. for 45 minutes, and then heated on a steam bath for 45 minutesunder nitrogen. Evaporation under vacuum yielded the isocyanate compoundas a clear oil. IR: 2250 cm (strong). The isocyanate compound was takenup in bromobenzene (40 mL) and added dropwise to a stirred mixture ofaluminum chloride (3.10 g) in bromobenzene (80 mL) at 100° C. undernitrogen. The reaction temperature was raised to 150° C., and thereaction was stirred for one hour. The reaction was poured intoice/water (250 g) and filtered. The layers of the biphasic filtrate wereseparated, and the organic layer was evaporated under vacuum. Theaqueous filtrate was extracted once with ethyl acetate, and the ethylacetate extract was then combined with the residue from the evaporatedorganic layer. The resulting solution was washed with water, saturatedsodium bicarbonate, water, 1 N HCl, and brine, dried over magnesiumsulfate, and evaporated under vacuum. Flash chromatography throughsilica gel 60 using 4:1 chloroform:ethyl acetate yielded the titlecompound as a white solid. Mp: 164°-165° C.

(d) 10,11-dihydro-8-methoxydibenz[b,][1,4]oxazepine

A solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 34 mL)was added dropwise under nitrogen to a stirred solution of the titlecompound of Example 16(c) (2.7 g) in tetrahydrofuran (60 mL) in an icewater bath keeping the temperature below 10° C. The ice bath wasremoved, and the reaction was stirred at reflux for 4.5 hours. Theresulting mixture was cooled to approximately 1° C. and quenched by thesuccessive addition of water (1.3 mL), 15% NaOH (1.3 mL), and water (3.9mL). The reaction was filtered through celite, and the filtrate wasevaporated under vacuum to a light orange solid. Flash chromatographythrough silica gel 60 using 3:1 hexane:ethyl acetate yielded the titlecompound as a pinkish-white solid. Mp: 110°-112° C.

(e) 8-methoxydibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a stirred solution of phosgene (1.93 M in toluene, 8.4 mL) intetrahydrofuran (40 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example16(d) (2.00 g) and triethylamine (1.3 mL) in tetrahydrofuran (15 mL).The ice bath was removed, and the reaction was stirred at ambienttemperature for 1.5 hours. The reaction was evaporated under vacuum, andto the residue Was added 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide(1.59 g), triethylamine (1.3 mL), and toluene (50 mL). The reactionmixture was refluxed for 2 hours, stirred for 16 hours at roomtemperature, and then evaporated under vacuum. The residue waspartitioned between ethyl acetate and 1 M HCl, and the undissolvedproduct was collected by filtration, washed with 1 N HCl, water, andether, and set aside. The layers of the biphasic filtrate wereseparated, and the aqueous layer was extracted once more with ethylacetate. The ethyl acetate extracts were combined and washed with 1 MHCl, water, saturated sodium bicarbonate, and brine, dried overmagnesium sulfate, and evaporated under vacuum. This was combined withthe undissolved product collected earlier and recrystallized fromethanol (3A) to yield the pure title compound as white crystals. Mp:187°-190° C.

EXAMPLE 17 8-methyldibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR32##4-methyl-2-nitro-1-phenoxybenzene

Sodium hydride (2.94 g) was added in portions to a solution of phenol(10.97 g) in N,N-dimethylformamide (75 mL) in a room temperature waterbath under nitrogen. The water bath was removed, and to the darksolution was added copper powder (0.74 g), 4-chloro-3-nitrotoluene (10.0g) and N,N-dimethylformamide (25 mL). The mixture was heated to 125° C.for 16 hours and evaporated under vacuum. The residue was partitionedbetween chloroform and water, and the layers were separated. Thechloroform layer was washed with 1 N NaOH, water, and brine, dried overmagnesium sulfate, and evaporated under vacuum. The crude oil wasdistilled under vacuum, and a fraction boiling at 148° C. (0.25 mm Hg)was collected to yield the title compound as a yellow oil.

(b) 5-methyl-2-phenoxybenzeneamine

A solution of the title compound of Example 17(a) (7.5 g) in methanol(30 mL) was shaken in a Parr Hydrogenator over 5% palladium on carbon at5 psi hydrogen at room temperature for 18 hours. The catalyst wasfiltered from the reaction, and the solution was evaporated under vacuumto yield the title compound as a yellow oil.

(c) 8-methyldibenz[b,f][1,4]oxazepin-11(10H)-one

To a solution of phosgene (1.93 M in toluene, 65 mL) under nitrogen atapproximately 5° C. was added dropwise a solution of5-methyl-2-phenoxybenzeneamine (5.0 g) in toluene (15 mL). The resultingsolution was stirred at 0°-5° C. for 30 minutes, and heated on a steambath for 35 minutes under nitrogen. Evaporation under vacuum yielded theisocyanate compound as a clear oil. IR: 2250 cm (strong). The isocyanatecompound was taken up in bromobenzene (30 mL) and added dropwise to astirred mixture of aluminum chloride (3.35 g) in bromobenzene (30 mL) at100° C. under nitrogen. The reaction temperature was raised to 150° C.,and the reaction was stirred for one hour. The reaction was poured intoice/water (250 g) and extracted twice with chloroform. The combinedchloroform extracts were washed with water, 1 N HCl, saturated sodiumbicarbonate, and brine, dried over magnesium sulfate, and evaporatedunder vacuum. The residue was suspended in ether, and the insolubleproduct was collected by filtration and washed with ether to yield thetitle compound as white crystals. Mp: 231°-232° C.

(d) 10,11-dihydro-8-methyldibenz[b,f][1,4]oxazepine

A solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 60 mL)was added dropwise under nitrogen to a stirred solution of the titlecompound of Example 17(c) (4.5 g) in tetrahydrofuran (300 mL) in an icewater bath, keeping the temperature below 10° C. The ice water bath wasremoved, and the reaction was stirred at ambient temperature for 45minutes. The reaction was then refluxed for 4.5 hours, and the resultingmixture was cooled to approximately 5° C. and quenched by the successiveaddition of water (2.3 mL), 15% NaOH (2.3 mL), and water (6.9 mL). Thereaction was filtered, and the filtrate was evaporated under vacuum to acloudy oil which solidified on standing. The solid was taken up inchloroform, and the solution was washed with 1 N NaOH, water, and brine,dried over magnesium sulfate, and evaporated under vacuum. Flashchromatography through silica gel 60 using chloroform yielded the titlecompound as a yellowish-white, waxy solid. Mp: 84°-86° C.

(e) 8-methyldibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a stirred solution of phosgene (1.93 M in toluene, 9.0 mL) intetrahydrofuran (40 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example17(d) (2.00 g) and triethylamine (1.4 mL) in tetrahydrofuran (40 mL).The ice bath was removed, and the reaction was stirred at ambienttemperature for 2 hours. The reaction was evaporated under vacuum, andto the residue was added 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide(1.71 g), triethylamine (1.4 mL), and toluene (50 mL). The reactionmixture was refluxed for 1.5 hours, and evaporated under vacuum. Theresidue was partitioned between chloroform and water, and the layerswere separated, and the chloroform layer was washed with water, 1 N HCl,water, saturated sodium bicarbonate, and brine, dried over magnesiumsulfate, and evaporated under vacuum to a yellow solid.Recrystallization from ethanol (3A) yielded the pure title compound as awhite solid. Mp: 167°-169° C.

EXAMPLE 18 4-chlorodibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR33## (a)2-chloro-1-(2-nitrophenoxy)benzene

Sodium hydride (1.00 g) was added in portions to a solution of2-chlorophenol (5.00 g) in N,N-dimethylformamide (100 mL) undernitrogen. To the resulting solution was added 2-fluoro-1-nitrobenzene(5.00 g). The mixture was heated at 65° C. overnight, and then wasevaporated under vacuum. The residue was partitioned between chloroformand 1 N NaOH, and the layers were separated. The aqueous layer wasextracted once more with chloroform, and the combined chloroform layerswere washed with water and brine, dried over magnesium sulfate, andevaporated under vacuum to a yellow oil. The oil was crystallized fromethyl ether/hexane at -78° C. to yield the title compound as a lightyellow solid. Mp: 48°-49° C.

(b) 2-(2-chlorophenoxy)benzeneamine

A solution of 2-chloro-(2-nitrophenoxy)benzene (5.00 g) intetrahydrofuran (100 mL) was shaken in a Parr Hydrogenator over Raneynickel at 5 psi hydrogen at room temperature for 4 hours. The catalystwas filtered from the reaction, and the solution was evaporated undervacuum to a yellowish oil which crystallized on standing. The solid wascrushed, suspended in hexane and filtered to yield the title compound asa light orange solid. Mp: 44°-45° C.

(c) 4-chlorodibenz[b,f][1,4]oxazepin-11(10H)-one

To a solution of phosgene (1.93 M in toluene, 42 mL) under nitrogen atapproximately 5° C. was added dropwise a solution of the title compoundof Example 18(b) (3.50 g) in toluene (11 mL). The mixture was stirred at0°-5° C. for 30 minutes, and then heated on a steam bath for 30 minutesunder nitrogen. Evaporation under vacuum yielded the isocyanate compoundas a clear oil. IR: 2250 cm (strong). The isocyanate compound was takenup in bromobenzene (2; mL) and added dropwise to a stirred mixture ofaluminum chloride (2.14 g) in bromobenzene (21 mL) at 100° C. undernitrogen. The reaction temperature was raised to 150° C., and thereaction was stirred for two hours. The reaction was evaporated undervacuum, and the residue was vigorously shaken with ethyl acetate/1 NNaOH. The resulting emulsion was filtered through a sintered glassfunnel, and the resulting layers were separated. The semi-solid whichhad collected on the filter was washed with ethyl acetate, and this washwas combined with the ethyl acetate from the filtrate. The ethyl acetatelayers were combined, washed with 1 N NaOH, 1 N HCl, and brine, driedover magnesium sulfate, and evaporated under vacuum to an oily, solid,yellow residue. This was triturated with ethyl ether, and the solid wascollected by filtration. This solid was added to the semi-solidcollected earlier, and the combined solids were washed with ether andair dried. The crude product was refluxed with ethanol (3A, 200 mL) forone hour, evaporated to dryness, triturated with ethyl ether, and thesolid was collected. Drying under vacuum at 56° C. yielded the titlecompound as a white solid.

(d) 4-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine

A solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 60 mL)was added dropwise under nitrogen to a stirred solution of the titlecompound of Example 18(c) (3.00 g) in tetrahydrofuran (100 mL) in an icewater bath keeping the temperature below 15° C. The ice bath wasremoved, and the reaction was stirred at reflux for 3.5 hours, and theresulting mixture was cooled to approximately 5° C. and quenched by thesuccessive addition of water (2.3 mL), 15% NaOH (2.3 mL), and water (6.9mL). The reaction was filtered, and the solid was rinsed withtetrahydrofuran. The rinse and filtrate were combined and evaporatedunder vacuum. Flash chromatography through silica gel 60 using 4:1hexane:ethyl acetate yielded the title compound as an oil whichsolidified on standing to a white solid. Mp: 71°-73° C.

(e) 4-chlorodibenz[b,f]1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide

To a stirred solution of phosgene (1.93 M in toluene, 6.5 mL) intetrahydrofuran (30 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of the title compound of Example18(d) (1.50 g) and triethylamine (1.0 mL) in tetrahydrofuran (20 mL).The ice bath was removed, and the reaction was stirred at ambienttemperature for 2 hours. The reaction was evaporated under vacuum, andto the residue was added 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide(1.28 g), triethylamine (1.0 mL), and toluene (35 mL). The reactionmixture was refluxed for 3 hours under nitrogen and evaporated undervacuum until most of the toluene had been removed. The residue wastreated with ethyl ether, and the precipitated solid was collected byfiltration. The solid was washed with ethyl ether, suspended in 1 N HCl(25 mL), and heated on a steam bath for 5 minutes. After cooling to 5°C., the insoluble crude product was collected by filtration, washed withethyl ether, and crystallized from ethanol (3A) to yield the titlecompound as white crystals. Mp: 195°-197° C.

EXAMPLE 19 8-hydroxydibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR34##

To a stirred solution of boron tribromide (1.0 M in methylene chloride,7.2 mL) at 5° C. (ice water bath) was added under nitrogen the titlecompound of Example 16(e) (1.0 g). The ice bath was removed, and thereaction was stirred at room temperature for 3 hours. The reaction wascarefully quenched by the addition of 1 N NaOH (10 mL), acidified by theaddition of 1 N HCl (15 mL), and evaporated under vacuum. The resultingsolid was triturated with water, and the insoluble material wascollected by filtration, washed three times with water, and then withethyl ether. Crystallization from ethanol (3A) yielded the titlecompound as white crystals. Mp: 191°-194° C.

EXAMPLE 20 8-(trifluoromethyl)dibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR35##

200 parts of 4-chloro-3-nitrobenzotrifluoride was heated to 160° C. andstirred and 160 parts of the potassium salt of salicylaldehyde was addedover a period of 30 minutes. After the addition was complete, anexothermic reaction took place and the temperature rose to about 195° C.Heating was then discontinued until the reaction subsided, and themixture was then heated for 1 hour at 150° C. The mixture was cooled,ice and water were added, and it was then extracted with ether. Theether layer was filtered to remove insoluble material, and the resultantsolution was dried over sodium sulfate. The ether solvent was thenevaporated and the residual oil was recrystallized from a mixture ofhexane and benzene to give2-(2-nitro-4-trifluoromethylphenoxy)benzaldehyde melting at about79°-81° C.

A solution of 55 parts of the ether obtained in the preceding paragraphin 800 parts of ethanol was hydrogenated over Raney nickel catalyst atroom temperature and atmospheric pressure. When hydrogen uptake ceased,the catalyst was removed by filtration and the ethanol solvent wasevaporated. The residue was then dissolved in 500 parts by volume ofhexane, filtered, and then cooled. There was then obtainedyellowish-white crystals which were separated by filtration to give8-(trifluoromethyl)10,11,-dihydrodibenz -[b,f][1,4]oxazepine melting atabout 86°-88° C.

To a stirred solution of phosgene (1.93 M in toluene, 5.4 mL) intetrahydrofuran (23 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of8-(trifluoromethyl)-10,11-dihydrodibenz[b,f][1,4]oxazepine (1.50 g) andtriethylamine (0.8 mL) in tetrahydrofuran (14 mL). The ice bath wasremoved, and the reaction was stirred at ambient temperature for 1 hour.The reaction was evaporated under vacuum, and to the residue was added2-[3- ethylsulfonyl)-1-oxopropyl]hydrazide (1.03 g), triethylamine (0.8mL) and toluene (28 mL). The reaction mixture was refluxed for 2 hours,and stirred at room temperature for 16 hours. The reaction was dilutedwith ether, and the precipitate was collected by filtration. Afterwashing with ether, the precipitate was suspended in water, heated on asteam bath for 5 minutes, and cooled to room temperature. The insolubleproduct was collected by filtration, washed with water followed byether, and crystallized from toluene to yield the desired title compoundas a white powder. Mp: 139°-145° C.

EXAMPLE 21 Dibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR36##

A solution of 2.0 g of 8-chloro-10,11-dihydrodibenz [b,f][1,4]oxazepine,0.77 g of sodium hydroxide, and 5% palladium on carbon in 50 mL ofethanol (3A) was shaken at 60 psi hydrogen in a Parr hydrogenator atroom temperature for 3.67 hours. The catalyst was filtered from thereaction and the solution was evaporated under vacuum. The residue wastaken up in chloroform, washed with water and brine, dried overmagnesium sulfate, and evaporated under vacuum to yield 1.16 g (68.1%)of 10,11-dihydrodibenz[b,f][1,4]oxazepine as a tan solid. Mp: 74°-76° C.

To a stirred solution of phosgene (1.93 M in toluene, 4.8 mL) intetrahydrofuran (20 mL) at approximately 5° C. (ice water bath) undernitrogen was added dropwise a solution of10,11-dihydrodibenz[b,f][1,4]oxazepine (1.0 g) and triethylamine (0.73mL) in tetrahydrofuran (12 mL). The ice bath was removed, and thereaction was stirred at ambient temperature for 2 hours. The reactionwas evaporated under vacuum, and to the residue was added2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (0.914 g), triethylamine (1.6mL), and toluene (25 mL). The reaction mixture was refluxed for 2 hoursand evaporated under vacuum. The residue was partitioned betweenchloroform and water, the layers were separated, and the chloroformlayer was washed with water and brine, dried over magnesium sulfate, andevaporated under vacuum. The crude product was flash chromatographedthrough silica gel 60 using chloroform. Crystallization of thechromatographed product yielded the pure product as a white solid. Mp:173°-177° C.

EXAMPLE 22 8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazeoine-10-(11 H)carboxylic acid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR37##(a) 4-chloro-2-nitro-1-(phenylthio)benzene

Potassium hydroxide (6.15 g; 87%) was added to a stirred solution ofthiophenol (10.0 g) in N,N-dimethylformamide (170 mL) at roomtemperature. When most of the potassium hydroxide appeared to havedissolved, 2,5-dichloronitrobenzene (17.4 g) was added, and theinitially dark solution turned a bright yellow with some precipitate.The reaction was placed in an oil bath at 70° C. for three hours, andthen evaporated in vacuo. The residue was partitioned between chloroformand 1 N NaOH and the layers were separated. The aqueous layer wasextracted once more with chloroform. The chloroform solutions werecombined, washed with 1 N NaOH, H₂ O, 1 N HCl, H₂ O and brine, driedover MgSO₄, and evaporated in vacuo. The resulting oil was treated withcyclohexane, and the product crystallized. The crystalline product wascollected by filtration, washed with hexane, and dried in vacuo at 56°C. to yield 13.73 g (57%) of yellow crystals. mp: 84°-86° C.

(b) 5-chloro-2(phenylthio)benzenamine

A solution of 4-chloro-2-nitro-1-(phenylthio)benzene (11.0 g) and Raneynickel in ethanol (3A; 9.3 mL) was reacted in a Parr Hydrogenator underhydrogen atmosphere at 5 psi and room temperature. When the theoreticalamount of hydrogen uptake was reached, the reaction was filtered toremove the catalyst and evaporated in vacuo to yield 8.61 g (88%) of alight orange solid. mp: 59°-61° C.

(c) 8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepine

To a cold (ice water bath), stirred solution of phosgene (1.93 M intoluene; 55 mL) under a nitrogen atmosphere was added, dropwise, asolution of 5-chloro-2-(phenylthio)benzenamine (5.00 g) in toluene (20mL). The reaction mixture was stirred for 30 minutes in the ice bath,and was then heated on a steam bath for 30 minutes. The resulting orangesolution was evaporated in vacuo to an oil (IR: weak band atapproximately 2250 cm⁻¹).

The oil was taken up in bromobenzene 25 mL) and added dropwise to astirred mixture of aluminum chloride (2.90 g) in bromobenzene (25 mL) inan oil bath at 100° C. When the addition was complete, the oil bathtemperature was increased to 150° C., and the reaction was stirred for1.5 hours. A small amount of water was then added to quench thereaction, and the mixture was evaporated in vacuo. The residue wastriturated with acetone, and the solid was collected by filtration,washed with acetone followed by ether, and dried in vacuo at 110° C. for16 hours to yield 6.99 of white solid.

The white solid (6.64 g) was suspended with stirring in anhydroustetrahydrofuran (175 mL) under a nitrogen atmosphere in an ice-H₂ Obath, and lithium aluminum hydride (1.0 M in THF; 100 mL) was addeddropwise, keeping the temperature below 10° C. When the addition wascomplete, the ice bath was removed and the reaction stirred to roomtemperature (approximately 20 minutes), and then at reflux for fourhours under a nitrogen atmosphere. The reaction was then cooled in anice-H₂ O bath and quenched by the successive addition of H₂ O (3.8 mL),15% NaOH (3.8 mL), and H₂ O (11.4 mL) while keeping the temperaturebelow 15° C. The resulting mixture was filtered through filter aide andthe filter cake was washed with THF. The filtrate and washes werecombined and evaporated in vacuo to a yellow oil. The oil was flashchromatographed through silica gel 60 (approximately 300 mL) usingchloroform. The collected product was recrystallized from cyclohexane toyield 2.37 g (42.7%) of product as white plates. mp: 125°-127° C.

(d) 8-chloro-10,11-dihydrodibenzo[b,f][1,4]-thiazeoine -10(11H)-carboxylic acid, 2-[3-(ethylsulfonyl) -1-oxopropyl]-hydrazide

To a cold (ice-H₂ O bath), stirred solution of phosgene (1.93 M intoluene; 8.6 mL) in anhydrous tetrahydrofuran (40 mL) under a nitrogenatmosphere was added, dropwise, a solution of8-chloro-10,11-dihydrodibenzo[b,f][1,4]-thiazepine (2.00 g) andtriethylamine (1.3 mL) in anhydrous tetrahydrofuran (30 mL). Theresulting mixture was stirred at room temperature for 90 minutes, andthe solvent was then evaporated in vacuo. To the residue was addedtoluene (50 mL), 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (1.53 g),and triethylamine (1.3 mL), and the reaction was stirred at reflux undera nitrogen atmosphere for 3.5 hours, and then at room temperatureovernight. The reaction was diluted with ethyl ether (100 mL) and theundissolved material collected by filtration. The collected material waswashed with ether, suspended in H₂ O (50 mL), and heated on a steam bathfor 5 minutes. The undissolved material was again collected byfiltration and was washed with H₂ O followed by ether. After air dryingfor one hour, the crude product was flash chromatographed through silicagel 60 (approximately 350 mL) using 3:1 chloroform:tetrahydrofuran. Thisproduct was chromatographed a second time via medium pressurechromatography through silica gel 60 using 95:5 chloroform:methanol. Thecollected product was dried in vacuo at 56° C. for 48 hours to yield2.20 g (60.0%) of the desired title compound of Example 22 as asolidified foam.

Analysis calculated for C₁₉ H₂₀ ClO₄ S₂ : C, 49.24; H, 4.35; N, 9.02;Cl, 9.89; S, 13.76. Found: C, 48.84; H, 4.29; N, 9.03; Cl, 9.64; S,13.96. HPLC: 100%.

EXAMPLE 23 8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepine-10 (11 H)carboxylic acid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide, 5,5-dioxide##STR38##

To a cold (ice-H₂ O bath), stirred solution of the title compound ofExample 22 )0.75 g) in methylene chloride (15 mL) was added a solutionof m-chloroperoxybenzoic acid (55%; 1.05 g) in methylene chloride (15mL). The solution was stirred in the ice bath for 3.5 hours, dilutedwith chloroform, and washed with saturated NaHSO₃ (2×200 mL), saturatedNaHCO₃ (2×200 mL), and brine (200 mL). The solution was dried over MgSO₄and evaporated in vacuo. The crude product was flash chromatographedthrough silica gel 60 (approximately 300 mL) using 1:1chloroform:tetrahydrofuran. The purified product was taken up in ethanol(3A) and evaporated in vacuo to yield a white solid. Recrystallizationfrom ethanol (3A) yielded 303 mg (37.7%) of the desired title compoundas white crystals.

Analysis calculated for C₁₉ H₂₀ ClO₆ S₂ : C, 46.96; H, 4.15; N, 8.65;Cl, 7.30; S, 13 20. Found: C, 46.87; H, 4.22; N, 8.61; Cl, 7.31; S,13.06. HPLC: 99.06%. DSC: 218°-219° C.

The identity and purity of the products synthesized in the examplespresented above were confirmed by ¹ H NMR, ¹³ C NMR, microanalysis, andhigh performance liquid chromatography (HPLC). The results of theseanalyses are presented in Table 1 below.

                                      TABLE 1                                     __________________________________________________________________________    Analytical Data                                                               Elemental Analysis                                                            Example                                                                            % C    % H    % N    % Cl   % S     HPLC                                                                              Mp                               Number                                                                             Calc.                                                                            Found                                                                             Calc.                                                                            Found                                                                             Calc.                                                                            Found                                                                             Calc.                                                                            Found                                                                             Calc.                                                                             Found                                                                             (%) (°C.)                     __________________________________________________________________________     5   56.23                                                                            56.04                                                                             5.90                                                                             5.97                                                                              8.19                                                                             7.77                                                                               --*                                                                             --  --  --  97.64                                                                             130-142                           3(d)                                                                              57.24                                                                            57.58                                                                             5.80                                                                             5.99                                                                              8.34                                                                             7.74                                                                              -- --  --  --  99.66                                                                             --                                2   54.66                                                                            54.75                                                                             5.02                                                                             5.09                                                                              9.10                                                                             9.01                                                                              -- --  6.95                                                                              6.80                                                                              99.09                                                                             211-212                           1(e)                                                                              54.66                                                                             1.09                                                                             5.02                                                                             5.04                                                                              9.11                                                                             9.03                                                                              -- --  6.95                                                                              7.07                                                                              100.0                                                                             172-176                           7(c)                                                                              54.14                                                                            53.76                                                                             4.78                                                                             4.79                                                                              9.97                                                                             9.85                                                                              -- --  --  --  99.80                                                                             191-193                           8(c)                                                                              56.56                                                                            55.78                                                                             5.25                                                                             5.32                                                                              10.42                                                                            10.13                                                                             -- --  --  --  99.90                                                                             184-185                           9(c)                                                                              48.31                                                                            48.25                                                                             4.05                                                                             4.01                                                                              8.90                                                                             8.95                                                                              -- --  --  --  99.93                                                                             189-190                           6   53.69                                                                            53.47                                                                             4.73                                                                             4.92                                                                              9.39                                                                             9.05                                                                              -- --  --  --  100.0                                                                             185-191                           4   53.68                                                                            53.48                                                                             4.73                                                                             4.72                                                                              9.39                                                                             9.31                                                                              -- --  --  --  98.97                                                                             191-194                          10(d)                                                                              50.89                                                                            50.79                                                                             4.50                                                                             4.52                                                                              12.49                                                                            12.50                                                                             -- --  7.15                                                                              7.10                                                                              99.95                                                                             198-200                          11(d)                                                                              56.07                                                                            56.04                                                                             4.70                                                                             4.80                                                                              13.08                                                                            13.19                                                                             -- --  --  --  99.91                                                                             188-190                          12(d)                                                                              52.12                                                                            51.74                                                                             4.60                                                                             4.65                                                                              9.60                                                                             9.32                                                                              -- --  --  --  100.0                                                                             209-211                          13   54.54                                                                            54.48                                                                             5.30                                                                             5.38                                                                              13.39                                                                            13.31                                                                             -- --  7.66                                                                              7.63                                                                              99.14                                                                             172-179                          14   48.38                                                                            48.44                                                                             4.87                                                                             4.85                                                                              11.28                                                                            11.53                                                                             -- --  12.91                                                                             12.75                                                                             100.0                                                                             211-212                          15   57.12                                                                            57.28                                                                             6.46                                                                             6.41                                                                              11.59                                                                            11.52                                                                             -- --  --  --  99.53                                                                             --                               16(e)                                                                              55.42                                                                            55.30                                                                             5.35                                                                             5.40                                                                              9.69                                                                             9.62                                                                              -- --  --  --  99.03                                                                             187-190                          17(e)                                                                              57.54                                                                            57.49                                                                             5.55                                                                             5.51                                                                              10.06                                                                            10.00                                                                             -- --  --  --  99.81                                                                             167-169                          18(e)                                                                              52.12                                                                            52.21                                                                             4.60                                                                             4.61                                                                              9.60                                                                             9.58                                                                              8.10                                                                             8.14                                                                              7.32                                                                              7.38                                                                              100.0                                                                             195-197                          19   54.41                                                                            54.51                                                                             5.05                                                                             5.06                                                                              10.02                                                                            10.06                                                                             -- --  7.64                                                                              7.39                                                                              99.50                                                                             191-194                          20   50.95                                                                            50.65                                                                             4.28                                                                             4.18                                                                              8.91                                                                             8.79                                                                              -- --  6.80                                                                              6.98                                                                              99.70                                                                             139-145                          21   56.56                                                                            55.78                                                                             5.25                                                                             5.32                                                                              10.42                                                                            10.13                                                                             -- --  7.95                                                                              7.74                                                                              98.86                                                                             173-177                          __________________________________________________________________________     *Indicates that chlorine and sulfur were not present in the compound and,     thus, that no analyses were performed for these elements.                

The foregoing examples are provided to enable one of ordinary skill inthe art to practice the present invention. These examples are merelyillustrative, however, and should not be read as limiting the scope ofthe invention as it is claimed in the appended claims.

(7) The Writhing Assay

The Writhing Assay is one of the most widely-used experimentalprocedures for measuring the analgesic activity of different narcoticand nonnarcotic analgesic agents, and involves the continuous,chemically-induced pain of visceral origin to an animal, such as a mouseor rat. [Gyires et al., Arch. int. Pharmacodyn, 267, 131-140 (1984); C.Vander Wende et al., Fed. Proc., 15, 494 (1956); Koster et al., Fed.Proc., 18, 412 (1959); and Witken et al., J. Pharmacol. exp. Ther., 133,400-408 1961).] Chemicals which may be used to induce this pain includephenylbenzoquinone (PBQ) and acetic acid. As a result of the chemicalirritation to the animal, a characteristic stretching and writhing ofthe animal (dorsiflexion of the animal's back, extension of itshindlimbs and the strong contraction of its abdominal musculature) willgenerally occur. The intensity of this pain reaction is determined bythe number of writhes exhibited by the animal during a given period oftime. Drugs which reduce the number of writhes of the animal appear torestore the normal nociceptive threshold of the animal.

Compounds of the present invention exhibit analgesic activity in mice,as shown by the results of the Writhing Assay presented in Table 2below.

Charles River male albino mice, weighing 20 to 30 grams were used inthis assay.

Twenty-five minutes after subcutaneous or intragastric administration toten mice of 30 mg per kilogram of body weight of a compound of thepresent invention ("test compound"), 0.1 mg per 10 g of body weight of a0.025% w/v solution of PBQ was injected intraperitoneally into eachmouse. Ten mice which were given saline in place of a test compound ofthe invention were used as a control group.

Five minutes later, each mouse was individually placed into a glassbeaker for observation, and the number of writhes occurring during thefollowing ten-minute period was counted.

A test compound was considered to have produced analgesia in a mouse if,in accordance with the conditions set forth above, and under the testcriteria employed for this assay, after the administration of 30 mg perkilogram of body weight of a compound of the present invention to themouse, the number of writhes elicited by a mouse injected with PBQ wasequal to, or less than, one-half the median number of writhes recordedfor the saline-treated control group of mice that day, as described byTaber in "Predictive Value of Analgesic Assays in Mice and Rats,"Advances in Biochemical Psychopharmacology, 8, 191 1974).

The results for the particular compounds of the present inventionanalyzed in this assay, and discussed in the examples identified belowwhich correspond thereto, are presented in Table 2 hereinbelow under theheading "WRITHING ASSAY." The fractions indicate the number of mice outof ten in which a test compound produced analgesia.8-(trifluoromethyl)dibenz[b,f][1,4]oxazepine-10(11 H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (Example 20) was determinedto be the most potent compound of the invention tested in this assay,and is the most preferred compound of the present invention.

(b) Prostaglandin (PGE) Antagonism Assay

In order to determine the effectiveness of several of the compounds ofthe present invention ("test compounds") as prostaglandin E₂antagonists, a prostaglandin antagonism assay was conducted, asdescribed below, to determine the ability of these compounds to inhibitprostaglandin E₂ -induced contractions of segments of guinea pig ileum.If a test compound inhibits prostaglandin E₂ -induced contractions, itsuggests that the compound functionally antagonizes prostaglandin E₂.

Male albino guinea pigs weighing 200 to 500 grams were sacrificed bycervical dislocation. The ilea were then quickly removed from the guineapigs and placed in a modified Tyrode solution, a solution which is knownto those skilled in the art, containing one-half of the usual amount ofmagnesium ions.

Segments of ileum about 2 cm long were then cut and mounted in a 10-mLtissue bath containing the modified Tyrode solution. The solution wasmaintained at 37° C. and aerated with a gaseous mixture of 95% oxygenand 5% carbon dioxide. Data for a control prostaglandin E₂ dose responsecurve plotting concentration of prostaglandin E₂ versus the intensity ofcontractions, detected isotonically, was then obtained by experimentallyadjusting the dose of the prostaglandin E₂ being injected into thetissue bath, in a manner known by those of skill in the art.

Solutions or suspensions containing an initial concentration (3micromolar) of a test compound in modified Tyrode solution ("testsolutions/suspensions") were then separately substituted for the controlbath solution. Each test solution/suspension was then kept in constantcontact with the ileum tissue, except for brief periods to drain thebath in preparation for rinsing with fresh test solution/suspension. Asecond prostaglandin E₂ dose response curve was then generated forprostaglandin E₂ in the presence of a test compound.

A dose ratio of EC₅₀ doses was then calculated from the results of eachtest in a manner known by those of skill in the art. A test compound wasdetermined to be "active" if the initial concentration used yielded atleast a two-fold shift (dose ratio greater than or equal to 2) in thedose response curve for prostaglandin E₂. An estimated pA₂ value (astatistical constant which is a common measure of expressing the potencyof a particular drug as an antagonist) was reported for "active"compounds under the assumption that the slope of the Schild plot doesnot deviate significantly from -1.0. If the initial concentration oftest compound yielded at least a five-fold shift (dose ratio greaterthan or equal to 5) in the dose response curve for prostaglandin E₂,then varying concentrations of the test compound were assayed, and a pA₂value for that compound was calculated by Schild plot calculations, asdescribed by H.O. Schild, "pA, A New Scale for the Measurement of DrugAntagonism," Br. J. pharmacol, 2, 189 (1947) . The higher the valuecalculated for the pA₂, the more potent a particular compound is as aprostaglandin E₂ antagonist.

The results of this prostaglandin antagonism assay are also presented inTable 2 below. The compounds of the present invention which were testedin this assay, and for which results are presented in Table 2,correspond to the particular examples specified in Table 2.

                  TABLE 2                                                         ______________________________________                                        Data Generated from the Assays                                                                         PGE ANTAGONISM                                               WRITHING ASSAY   IN GUINEA PIG                                        Example Number Out of Ten                                                                              ILEUM                                                Number  S.C.       I.G.      (pA.sub.2)                                       ______________________________________                                         5      3/10       2/10      5.93                                              3      3/10       4/10      5.75                                              2      3/10       3/9       5.70                                              1      5/10       3/10      5.54                                              7      6/10       4/10      *                                                 8      6/10       6/10      *                                                 9      3/10       4/10      5.8                                               6      2/10       4/10      5.58                                              4      4/10       3/10      *                                                10      4/10       4/10      5.54                                             11      5/10       5/9       *                                                12      4/10       3/10      5.94                                             13      4/10       4/10      5.55                                             14      6/10       6/10      *                                                15      1/10       3/10      6.15                                             16      2/10       6/10      5.70                                             17      2/10       2/9       5.68                                             18      4/10       4/10      5.57                                             19      3/10       4/10      5.59                                             20      6/10       6/10      5.9                                              21      1/10       5/10      5.98                                             22      3/10       6/10      **                                               23      7/10       3/10      **                                               ______________________________________                                         *Indicates that, in accordance with the particular conditions set forth       above in the Prostaglandin Antagonism Assay, and under the test criteria      employed for that assay, after the administration of an initial screening     dosage of 3 micromolar of the compound, a twofold shift in the dose           response curve for prostaglandin E.sub.2 was not yielded.                     **Not tested.                                                            

While the present invention has been described herein with somespecificity, and with reference to certain preferred embodimentsthereof, those of ordinary skill in the art will recognize numerousvariations, modifications and substitutions of that which has beendescribed which can be made, and which are within the scope and spiritof the invention. For example, effective dosages other than thepreferred ranges set forth hereinabove may be applicable as aconsequence of variations in the responsiveness of the animal beingtreated, dosage-related adverse effects, if any, and analogousconsiderations. Likewise, the specific pharmacological responsesobserved may vary according to, and depending upon, the particularactive compound selected, or whether there are present certainpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed. Such expected variations and/or differences inthe results are contemplated in accordance with the objects andpractices of the present invention. It is intended therefore that all ofthese modifications and variations be within the scope of the presentinvention as described and claimed herein, and that the invention belimited only by the scope of the claims which follow, and that suchclaims be interpreted as broadly as is reasonable.

What is claimed is:
 1. A compound of having the structure: ##STR39## 2.A compound having the structure: ##STR40##
 3. A compound having thestructure: ##STR41##